The invention relates to mycoplasma and Gram positive bacterial infections.
Gram-positive eubacteria contain three distinct DNA polymerase-exonucleases ("pol-exos"): Pol I, Pol II, and Pol III. Gram-positive Pol III is an enzyme which is absolutely required for the replicarive synthesis of DNA that accompanies the cyclical duplication of the host chromosome. The Gram-positive Pol IIIs are the exclusive targets of the Gram-positive-selective `HPUra` (6-(p-Hydroxyphenylazo)-uracil) class of antimicrobial agents, i.e., HPUra-like compounds. These agents exert their action by mimicking purine deoxyribonucleotide-triphosphates and physically inhibiting the DNA polymerases.
All known mycoplasmata are parasites of humans, vertebrates, plants, and arthropods. Species known or suspected to be human pathogens include M. pneumoniae, M. genitalium, M. penetrans, and, in AIDS patients especially, M. fermentans, strain incognitus. Mycoplasma infections in humans and animals are generally of a chronic nature and host immune reactions appear to play a major role in the pathogenesis of such infections. Especially problematic are autoimmunogenic responses elicited by mycoplasmal infections (e.g., rheumatoid-like arthritis, central nervous system symptoms and other types of organ dysfunction).
Mycoplasmata are the smallest and simplest prokaryotes capable of self-replication. They have arisen from conventional Gram-positive bacteria via rapid, degenerative evolution, apparently resulting in significant simplification of the typical Gram-positive genome. A mycoplasmal genome may be as small as 600 kb (but may be as large as 1700 kb) and carry fewer than 500 genes (about one fifth the number of genes as in E. coli). This simplified existence is made possible by parasitism.
It is thought that the genome reduction of mycoplasmata has affected the DNA polymerase family of enzymes, reducing the three exo-positive enzymes found in Gram-positive bacteria to a single exo-deficient species (Boxer et al., Biochemistry, 18:4742-49 (1979); Maurel et al., Res. Microbiol., 140:191-205 (1989); Mills et al., J. Bacteriol., 132:641-49 (1977)).
Previous investigations have identified only a single DNA polymerase in Mycoplasma. The enzyme from Mycoplasma orale has been purified and found to consist of a single peptide of 103-116 kDa, and a polymerase of the same size has been found in Mycoplasma hyorhinis. A 98 kDa polymerase also has been found in Mycoplasma mycoides. In contrast to the prototypic Gram-positive- and Gram-negative-specific pols I and II, both of which integrate the activity of at least one exo (3'-5' and/or 5'-3'), none of the previously described mycoplasmal enzymes is exo-positive.